Development of novel antibiotics targeting peptidases of non-fermenting gram negative rods.
Project/Area Number |
16H04902
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Applied microbiology
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Research Institution | Showa University |
Principal Investigator |
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Project Period (FY) |
2016-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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Keywords | 糖非発酵性細菌 / ペプチダーゼ / 立体構造 / 抗菌剤 / ドラッグデザイン |
Outline of Final Research Achievements |
Family S46 peptidases are widely distributed in anaerobic Gram-negative species in the genera Bacteroides, Parabacteroides, and Porphyromonas, but they are not found in mammals. Therefore, S46 peptidases are ideal targets for novel antibiotics. We determined a crystal structure of dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) in complex with citrate ions at a 1.50 Å resolution using a high-quality space-grown crystal. The bound citrate ion, a potassium ion, and a water molecule in the active site of PgDPP11 were regarded to mimic the binding of an acidic amino acid and were utilized as a pharmacophore for an in silico inhibitor screening. The screening resulted in the first nonpeptidyl inhibitor of S46 peptidases, SH-5. The binding mode of SH-5 was confirmed by crystal structure analysis at a 2.39 Å resolution. The hit compound SH-5 and a related compound represent promising lead structures for further rational design of potent inhibitors against PgDPP11.
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Academic Significance and Societal Importance of the Research Achievements |
歯周病原因菌Porphyromonas gingivalisや多剤耐性菌Stenotrophomonas maltophiliaは糖ではなく蛋白質やペプチドをエネルギー源とする「糖非発酵性細菌」である。従って、これらの菌のペプチド代謝経路を阻害するような化合物は新規抗生物質と成り得る。従って、本研究の学術的意義は、糖非発酵性細菌を標的とした新規抗生物質開発に繋がるものである。また、本研究の社会的意義として、製薬企業は感染症関連研究に対して消極的なため大学研究者による抗生物質開発に繋がる基盤研究は社会的に極めて重要であることを強調したい。
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Report
(4 results)
Research Products
(31 results)
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[Presentation] Elucidation of substrate recognition mechanism of dipeptidyl aminopeptidase IV from Gram-negative bacteria Pseudoxanthomonas mexicana WO242018
Author(s)
Akihiro Nakamura, Nobuyuki Honma, Saori Roppongi, Yoshiyuki Suzuki, Yosuke Shida, Yasumitsu Sakamoto, Koji Inaka, Hiroaki Tanaka, Kiyoito Kihira, Mitsugu Yamada, Izumi Yoshioka, Hiroaki Gouda, Takamasa Nonaka, Nobutada Tanaka, Wataru Ogasawara
Organizer
7th International GIGAKU conference in Nagaoka
Related Report
Int'l Joint Research
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[Presentation] Enzymatic characterization of S46 peptidase from pathogenic bacteria2017
Author(s)
Nobuyuki Honma, Yasuhiro Ito, Akihiro Nakamura, Saori Roppongi, Yuki Sakurai, Yoshiyuki Suzuki, Koushi Hidaka, Yuko Tsuda, Yasumitsu Sakamoto, Nobutada Tanaka, Wataru Ogasawara
Organizer
2017 1st STI-Gigaku
Related Report
Int'l Joint Research
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[Presentation] Crystal structures of dipeptidyl aminopeptidase IV from non-fermenting gram negative rods.2017
Author(s)
Roppongi, S., Tateoka, C., Suzuki, Y., Ito, Y., Fujimoto, M., Morisawa, S., Iizuka, I., Ogasawara, W., Tanaka, N., Sakamoto, Y., and Nonaka, T.
Organizer
International Union of Microbiological Societies 2017
Related Report
Int'l Joint Research
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[Presentation] S46 family bacterial dipeptidyl aminopeptidases as novel antibiotics targets.2017
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Ito, Y., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W., and Tanaka, N.
Organizer
International Union of Microbiological Societies 2017
Related Report
Int'l Joint Research
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[Presentation] Identification of substrate recognition residues in family S46 peptidase from pathogenic non-fermenting gram-negative bacteria.2017
Author(s)
Nakamura, A., Ito, Y., Suzuki, Y., Roppongi, S., Hidaka, K., Sakamoto, Y., Tanaka, N., and Ogasawara, W.
Organizer
International Union of Microbiological Societies 2017
Related Report
Int'l Joint Research
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[Presentation] Identification of Substrate Recognition Residues in Family S46 Peptidase from Gram-Negative Bacteria2017
Author(s)
Nakamura, A., Ito, Y., Suzuki, Y., Roppongi, S., Hidaka, K., Sakamoto, Y., Tanaka, N., and Ogasawara, W.
Organizer
6th International GIGAKU conference in Nagaoka
Related Report
Int'l Joint Research
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[Presentation] Analysis of Substrate Recognition Residues in Family S46 Peptidase from Gram-Negative Bacteria2017
Author(s)
Nakamura, A., Ito, Y., Suzuki, Y., Roppongi, S., Hidaka, K., Sakamoto, Y., Tanaka, N., and Ogasawara, W.
Organizer
2017 2nd STI-Gigaku
Related Report
Int'l Joint Research
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[Presentation] Identification of dipeptidic inhibitors targeting DPP7 derived from multiple drug resistant bacteria Stenotrophomonas maltophilia2017
Author(s)
Yuki Sakurai, Koushi Hidaka, Anna Miyazaki, Keiko Hojo, Saori Roppongi, Yasumitsu Sakamoto, Yasuhiro Ito, Yoshiyuki Suzuki, Wataru Ogasawara, Nobutada Tanaka, and Yuko Tsuda
Organizer
The 54th Japanese Peptide Symposium
Related Report
Int'l Joint Research
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[Presentation] Structural Analysis of Dipeptidyl Peptidase 11 (DPP11) from Porphyromonas gingivalis.2016
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
Organizer
AsCA 2016
Place of Presentation
Hanoi, Socialist Republic of Vietnam
Year and Date
2016-12-05
Related Report
Int'l Joint Research
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[Presentation] Structure and Fuctions of Dipeptidyl Peptidase 11 (DPP11) from Porphyromonas gingivalis.2016
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
Organizer
2nd International Symposium on Space Science of High Quality Protein Crystallization
Place of Presentation
Tokyo, Japan
Year and Date
2016-10-21
Related Report
Int'l Joint Research
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[Presentation] Crystal structure of dipeptidyl amino peptidase 11 from Porphyromonas gingivalis.2016
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
Organizer
42nd Naito Conference on In the Vanguard of Structural Biology
Place of Presentation
Sapporo, Japan
Year and Date
2016-10-06
Related Report
Int'l Joint Research
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[Presentation] Enzymatic characterization of S46 peptidase from pathogenic bacteria.2016
Author(s)
Ito, Y., Nakamura, A., Roppongi, S., Sakurai, Y., Suzuki, Y., Hidaka, K., Tsuda, Y., Sakamoto, Y., Tanaka, N. and Ogasawara, W.
Organizer
The 5th International GIGAKU Conference in Nagaoka
Place of Presentation
Nagaoka, Japan
Year and Date
2016-10-06
Related Report
Int'l Joint Research
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[Presentation] Crystal structure of dipeptidyl amino peptidase 11 (DPP11) from periodontal pathogen.2016
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
Organizer
ISS R&D 2016
Place of Presentation
San Diego, USA
Year and Date
2016-07-14
Related Report
Int'l Joint Research
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[Presentation] Crystal Structure analaysis of dipeptidyl peptidase 11 from Porphyromonas gingivalis.2016
Author(s)
Sakamoto, Y., Suzuki, Y., Iizuka, I., Tateoka, C., Roppongi, S., Fujimoto, M., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Gouda, H., Nonaka, T., Ogasawara, W. and Tanaka, N.
Organizer
16th International Conference on the Crystallization of Biological Macromolecules
Place of Presentation
Prague, Czech Republic
Year and Date
2016-07-05
Related Report
Int'l Joint Research
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[Presentation] Structure-Function Relationships of S46 Peptidases from Non-Fermenting Gram-Negative Rods.2016
Author(s)
Roppongi, S., Suzuki, Y., Iizuka, I., Inaka, K., Tanaka, H., Yamada, M., Ohta, K., Nonaka, T., Ogasawara, W., Tanaka, N. and Sakamoto, Y.
Organizer
116th The American Society for Microbiology General meeting
Place of Presentation
Boston, USA
Year and Date
2016-06-17
Related Report
Int'l Joint Research
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